前药
成纤维细胞活化蛋白
药品
细胞毒性T细胞
小分子
癌症研究
药理学
癌症
医学
化学
体外
生物化学
内科学
作者
Aureliano Zana,Andrea Galbiati,Ettore Gilardoni,Matilde Bocci,Jacopo Millul,Theo Sturm,Riccardo Stucchi,Abdullah Elsayed,Lisa Nadal,Martina Cirillo,Wolfgang Roll,Lars Stegger,Inga Asmus,Philipp Backhaus,Michael Schäfers,Dario Neri,Samuele Cazzamalli
标识
DOI:10.1158/1078-0432.ccr-22-1788
摘要
Small molecule drug conjugates (SMDC) are modular anticancer prodrugs that include a tumor-targeting small organic ligand, a cleavable linker, and a potent cytotoxic agent. Most of the SMDC products that have been developed for clinical applications target internalizing tumor-associated antigens on the surface of tumor cells. We have recently described a novel non-internalizing small organic ligand (named OncoFAP) of fibroblast activation protein (FAP), a tumor-associated antigen highly expressed in the stroma of most solid human malignancies.In this article, we describe a new series of OncoFAP-Drug derivatives based on monomethyl auristatin E (MMAE; a potent cytotoxic tubulin poison) and dipeptide linkers that are selectively cleaved by FAP in the tumor microenvironment.The tumor-targeting potential of OncoFAP was confirmed in patients with cancer using nuclear medicine procedures. We used mass spectrometry methodologies to quantify the amount of prodrug delivered to tumors and normal organs, as well as the efficiency of the drug release process. Linkers previously exploited for anticancer drug conjugates were used as benchmark. We identified OncoFAP-Gly-Pro-MMAE as the best performing SMDC, which has now been prioritized for further clinical development. OncoFAP-Gly-Pro-MMAE selectively delivered more than 10% injected dose per gram of MMAE to FAP-positive tumors, with a tumor-to-kidney ratio of 16:1 at 24 hours post-injection.The FAP-specific drug conjugates described in this article promise to be efficacious for the targeting of human malignancies. The extracellular release of potent anticancer payloads mediates durable complete remission in difficult-to-treat animal models of cancer.
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